Proteasome Inhibitor/Imatinib Combinations Exert Potentiated Antileukemia Efficacy But Not Cardiotoxicity In Chronic Myeloid Leukemia

Whether imatinib mesylate (IM)-based combinatory regimens could be an option for overcoming limitations of IM in treating chronic myeloid leukemia (CML), e.g., resistance developed by leukemic cells, unsatisfactory efficacy on patients at accelerated and blastic phases, and potential cardiotoxity, warrants further investigation. Here we report that the proteasome inhibitors, Bortezomib (BOR) and PSI, significantly potentiate proliferation/growth inhibition and enhance apoptotic effects of IM on K562 cells, CD34+ cells from CML patients, and BCR-ABL-expressing murine hematopoietic progenitor cells. BOR and PSI potentiate IM-triggered activation of caspases and inactivation of BCR-ABL oncoprotein, while caspase inhibitor blocks the apoptotic effect and reverse BCR-ABL inactivation. BOR/IM and PSI/IM combinations also attenuate DNA binding activity of NFκB. Intriguingly, low dose BOR/IM combination yields potent effects on inhibition of tumor growth, induction of apoptosis in leukemic cells, and inactivation of BCR-ABL oncoprotein, and does not cause weight loss or cardiotoxicity in null mice injected with K562 cells as compared to animals treated with IM at high doses. These results suggest a clinical trial to test the efficacy of IM/BOR combination in treating CML.